RESUMEN
New, highly stable tricyclic antitubercular ozonides 9 and 10 derived from artemisinin are reported in 39 and 9% yields, respectively. The ozonide groups of 9 and 10 were found to be stable under strong basic and acidic conditions. The absolute configuration of ozonides 9 was confirmed by X-ray crystallography. Ozonide 10 shows promising antitubercular activity against M. tuberculosis H37Ra and M. tuberculosis H37Rv with MIC values of 0.39 and 3.12 µg/mL, respectively.
Asunto(s)
Antimaláricos , Antituberculosos , Artemisininas , Compuestos Heterocíclicos/química , Mycobacterium tuberculosis/efectos de los fármacos , Antimaláricos/síntesis química , Antimaláricos/química , Antimaláricos/farmacología , Antituberculosos/síntesis química , Antituberculosos/química , Antituberculosos/farmacología , Artemisininas/síntesis química , Artemisininas/química , Artemisininas/farmacología , Cristalografía por Rayos X , Conformación Molecular , Estructura MolecularRESUMEN
Aervalanata possesses various useful medicinal and pharmaceutical activities. Phytochemical investigation of the plant has now led to the isolation of a new 2α,3α,15,16,19-pentahydroxy pimar-8(14)-ene diterpenoid (1) together with 12 other known compounds identified as ß-sitosterol (2), ß-sitosterol-3-O-ß-D-glucoside (3), canthin-6-one (4), 10-hydroxycanthin-6-one (aervine, 5), 10-methoxycanthin-6-one (methylaervine, 6), ß-carboline-1-propionic acid (7), 1-O-ß-D-glucopyranosyl-(2S,3R,8E)-2-[(2'R)-2-hydroxylpalmitoylamino]-8-octadecene-1,3-diol (8), 1-O-(ß-D-glucopyranosyl)-(2S,3S,4R,8Z)-2-[(2'R)-2'-hydroxytetracosanoylamino]-8(Z)-octadene-1,3,4-triol (9), (2S,3S,4R,10E)-2-[(2'R)-2'-hydroxytetracosanoylamino]-10-octadecene-1,3,4-triol (10), 6'-O-(4â³-hydroxy-trans-cinnamoyl)-kaempferol-3-O-ß-D-glucopyranoside (tribuloside, 11), 3-cinnamoyltribuloside (12) and sulfonoquinovosyldiacylglyceride (13). Among these, six compounds (8-13) are reported for the first time from this plant. Cytotoxicity evaluation of the compounds against five cancer cell lines (CHO, HepG2, HeLa, A-431 and MCF-7) shows promising IC50 values for compounds 4, 6 and 12.
Asunto(s)
Abietanos/química , Amaranthaceae/química , Abietanos/aislamiento & purificación , Línea Celular Tumoral , Diterpenos/química , Diterpenos/aislamiento & purificación , Humanos , Concentración 50 Inhibidora , Estructura MolecularRESUMEN
A new family of andrographolide analogues were synthesized and screened in vitro against kidney (HEK-293) and breast (MCF-7) cancer cells. The anti-cancer effects of the active analogues (2b, 2c and 4c) were determined by multiple cell based assays such as MTT, immunostaining, FACS, western blotting and transcriptional inhibition of NF-κB activity. Importantly, these compounds were found to possess higher anti-cancer potency than andrographolide and low toxicity to normal (VERO and MCF-10A) cells. Increased level of Bax/Bcl-xL ratio, caspase 3, and sub G1 population, higher expression level of tumor suppressor protein p53 and lower expression level of NF-κB suggested potent apoptotic property of the active analogues. Data revealed that the andrographolide derivative-mediated cell death in cancer cells was p53 dependent.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Diterpenos/síntesis química , Diterpenos/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/metabolismo , Caspasa 3/metabolismo , Línea Celular Tumoral , Técnicas de Química Sintética , Diterpenos/química , Diterpenos/metabolismo , Glutatión/metabolismo , Semivida , Humanos , Hidrólisis , FN-kappa B/metabolismo , Transcripción Genética/efectos de los fármacosRESUMEN
A new series of pyrrolo[3',4':3,4]pyrrolo[1,2-a]furoquinolines/phenanthrolines and pyrrolo[1,2-a]phenanthrolines were efficiently built up from an 8-hydroxyquinoline derivative or phenanthroline via 1,3-dipolar cycloaddition reaction involving non-stabilized azomethine ylides, generated in situ from the parent furo[3,2-h]quinoliniums/phenanthroliums, in presence of a copper(II) chloride-phenanthroline catalytic system. The methodology combines general applicability with high yields.
RESUMEN
An efficient chemoselective general procedure for the synthesis of γ-substituted ß,γ-unsaturated α-ketomethylthioesters from α,ß-unsaturated ketones has been achieved through an unprecedented PPh3 â HBr-DMSO mediated oxidative bromination and Kornblum oxidation sequence. The newly developed reagent system serves admirably for the synthesis of α-bromoenals from enals. Furthermore, AuCl3 -catalyzed efficient access to 3(2H)-furanones from the above intermediates under extremely mild conditions are described.
RESUMEN
A new general methodology for the synthesis of various functionalized privileged oxygen heterocyclic scaffolds, viz. pyrones, coumarins, and benzannulated coumarins, is developed. The synthesis proceeds through carbanion-induced ring transformation of lactones with various methylene carbonyl compounds followed by DDQ-mediated unprecedented oxidative cleavage of oxaylidenes intermediates. Studies of the mechanism of the conversions of oxaylidene intermediates into corresponding carbonyl compounds in the presence of DDQ revealed that the reactions took place via the formation of a Michael adduct instead of an intermolecular charge transfer complex. The methodology offers the fabrication of diverse privileged scaffolds with tolerance for many functional groups onto the oxygen heterocyclic molecular framework.
Asunto(s)
Cumarinas/síntesis química , Oxígeno/química , Pironas/síntesis química , Derivados del Benceno/síntesis química , Ciclización , Lactonas/síntesis química , Lactonas/química , Modelos MolecularesRESUMEN
A new series of bile acid-based trioxanes 23a-d, 24a-d, 25a-d, 26a, 26b, and 26d have been synthesized and assessed for their antimalarial activity against multidrug-resistant Plasmodium yoelii in Swiss mice by oral route. The antimalarial activity of these trioxanes showed a strong dependence on the side-chain length; shortening side-chain length lead to increase in activity. The antimalarial activity also showed even stronger dependence on the stereochemistry at C3 and C6 (C21 in Figure 5) of the trioxane moiety. Of the two diastereomers isolated of each of the trioxanes, more polar one was significantly more active than the less polar one. The more polar diastereomer of the trioxanes 26a, 26b, and 26d, were the most active compounds of the series. All these three trioxanes provided 100% protection at 24 mg/kg×4 days. In this model ß-arteether provided 100% and 20% protection at 48 mg/kg×4 days and 24 mg/kg×4 days, respectively.
Asunto(s)
Antimaláricos/síntesis química , Antimaláricos/farmacología , Ácidos y Sales Biliares/química , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/farmacología , Animales , Antimaláricos/química , Cristalografía por Rayos X , Resistencia a Múltiples Medicamentos , Compuestos Heterocíclicos/química , Espectroscopía de Resonancia Magnética , Ratones , Plasmodium yoelii/efectos de los fármacos , Espectrometría de Masa por Ionización de Electrospray , Espectrofotometría InfrarrojaRESUMEN
A 24-methylenecycloartane-3 ß, 16 ß, 23 ß-triol, Longitriol (1), rare bisclerodane imides, Longimide A (2) and previously known Longimide B (3) were isolated from ethanolic extract of the leaves of Polyalthia longifolia var. pendula. This is the first example of isolation of any cycloartane triterpene from this plant source. Structures were determined by extensive (1D and 2D NMR) spectroscopic data analysis combined with ESI MS/MS fragmentation and X-ray analysis. Furthermore, Compounds 1 and 2 were evaluated for their cytotoxic effects against four human cancer cell lines and found to be most active against cervical carcinoma cell lines with IC(50) value of 10.03 and 4.12 µg/mL, respectively.
Asunto(s)
Diterpenos/química , Polyalthia/química , Triterpenos/química , Línea Celular Tumoral , Diterpenos/aislamiento & purificación , Diterpenos/toxicidad , Humanos , Isomerismo , Espectroscopía de Resonancia Magnética , Conformación Molecular , Hojas de la Planta/química , Triterpenos/aislamiento & purificación , Triterpenos/toxicidadRESUMEN
A convenient synthesis of a new class of novel pyrazolo[3,4-d]pyrimidinophanes (four products, 41%), a new class of cyclophane, and X-ray structure of the first dissymmetrical [3.4]pyrazolo[3,4-d]pyrimidinophane (22%) are reported for the first time. The conformation of major syn product 6b is stabilized by weak pi-pi and O...Ar interactions.
Asunto(s)
Éteres Cíclicos/química , Éteres Cíclicos/síntesis química , Pirazoles/química , Pirazoles/síntesis química , Pirimidinas/química , Pirimidinas/síntesis química , Cristalografía por Rayos X , Modelos Moleculares , Estructura Molecular , EstereoisomerismoRESUMEN
A general and novel "bridged annulation" methodology for the synthesis of 5,6-dihydro-4H-benzo[kl]acridines has been developed via Michael addition of a conjugate base of 9-methyl-3,4-dihydroacridin-1(2H)-one to various cyclic or acyclic alpha,beta-unsaturated carbonyl/nitrile compounds under mild conditions at room temperature in a short time. To the best of our knowledge, such a general bridged annulation for the synthesis of fused N-heterocycles has not been reported in the literature.
Asunto(s)
Acridinas/síntesis química , Aldehídos/química , Nitrilos/química , Acridinas/química , Cristalografía por Rayos X , Ciclización , Modelos Moleculares , Estructura Molecular , Estereoisomerismo , TemperaturaRESUMEN
Concise chemical synthesis of a tetrasaccharide repeating unit of the O-antigen of Hafnia alvei 10457 is reported. Construction of the tetrasaccharide as its 4-methoxyphenyl glycoside was achieved by condensation of less abundant monosaccharide units such as, D-galactofuranose, N-acetyl-D-galactosamine and N-acetylneuraminic acid. The synthetic strategy consists of the preparation of suitably protected required monosaccharide intermediates from the commercially available reducing sugars and high yielding glycosylation reactions.
Asunto(s)
Hafnia alvei/química , Antígenos O/química , Oligosacáridos/síntesis química , Secuencia de Carbohidratos , Hafnia alvei/inmunología , Estructura Molecular , Oligosacáridos/químicaRESUMEN
An efficient and significantly rapid access of a series of glycosyl azides and glycosyl 1,2,3-triazole conjugates is reported using modified one-pot reaction conditions. In both cases yields were excellent and single diastereomers were obtained.
Asunto(s)
Azidas/síntesis química , Triazoles/síntesis química , Azidas/química , Glicosilación , Triazoles/químicaRESUMEN
A series of C-3 alkyl and arylalkyl 2,3-dideoxy hex-2-enopyranoside derivatives were synthesized by Morita-Baylis-Hillman reaction using enulosides 4, 5, and 6 and various aliphatic and aromatic aldehydes. The compounds were evaluated in vitro for the complete inhibition of growth of Mycobacterium tuberculosis H37Rv. They exhibited moderate to good activity in the range of 25-1.56 mug/mL. Among these, 4d, 4h, 5c, and 4hr showed activity at minimum inhibitory concentrations, 3.12, 6.25, 1.56, and 1.56 mug/mL, respectively. These compounds were safe against cytotoxicity in VERO cell line and mouse macrophage cell line J 744A.1. A QSAR analysis by CP-MLR with alignment-free 3D-descriptors indicated the relevance of structure space comparable to the minimum energy conformation (from conformational analysis) of 5c to the activity. The study indicates that the compounds attaining the conformational space of 5c and reflecting some symmetry, minimum eccentricity, and closely placed geometric and electronegativity centers therein are favorable for activity.
Asunto(s)
Antituberculosos/síntesis química , Glucósidos/síntesis química , Relación Estructura-Actividad Cuantitativa , Animales , Antituberculosos/química , Antituberculosos/farmacología , Línea Celular , Chlorocebus aethiops , Recuento de Colonia Microbiana , Cristalografía por Rayos X , Glucósidos/química , Glucósidos/farmacología , Ratones , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Conformación Molecular , Mycobacterium tuberculosis/efectos de los fármacosRESUMEN
A general, two-step, highly efficient synthesis of 1,2-diaryl-, 1,2,3-triaryl-, and 1,2,3,4-tetraarylbenzenes from simple stitching of alpha-oxo-ketene-S,S-acetals and active methylene compounds via a lactone intermediate is described. This procedure offers easy access to highly functionalized arylated benzenes that contain sterically demanding groups in good to excellent yields. The novelty of the procedure lies in the construction of aromatic compounds with the desired conformational flexibility along the molecular axis in a transition-metal-free environment through easily accessible precursors. Crystal analysis of these arylated benzene scaffolds showed that the peripheral aryl rings are arranged in a propeller-like fashion with respect to the central benzene ring. Examination of the crystal packing in the structure of a 1,2,3,4-tetraarylbenzene revealed an N...pi interaction between molecules related by a two-fold screw axis running in the direction of the a axis. Interestingly, the repeating array of N...pi interactions around the axis of this 1,2,3,4-tetraarylbenzene forces the molecules into a helical pattern.
Asunto(s)
Derivados del Benceno/síntesis química , Derivados del Benceno/química , Catálisis , Cristalografía por Rayos X , PaladioRESUMEN
Generation of phosphocholine by choline kinase is important for phosphatidylcholine biosynthesis via Kennedy pathway and phosphatidylcholine biosynthesis is essential for intraerythrocytic growth of malaria parasite. A putative gene (Gene ID PF14_0020) in chromosome 14, having highest sequence homology with choline kinase, has been identified by BLAST searches from P. falciparum genome sequence database. This gene has been PCR amplified, cloned, over-expressed and characterized. Choline kinase activity of the recombinant protein (PfCK) was validated as it catalyzed the formation of phosphocholine from choline in presence of ATP. The K(m) values for choline and ATP are found to be 145+/-20 microM and 2.5+/-0.3 mM, respectively. PfCK can phosphorylate choline efficiently but not ethanolamine. Southern blotting indicates that PfCK is a single copy gene and it is a cytosolic protein as evidenced by Western immunoblotting and confocal microscopy. A model structure of PfCK was constructed based on the crystal structure of choline kinase of C. elegans to search the structural homology. Consistent with the homology modeling predictions, CD analysis indicates that the alpha and beta content of PfCK are 33% and 14%, respectively. Since choline kinase plays a vital role for growth and multiplication of P. falciparum during intraerythrocytic stages, we can suggest that this well characterized PfCK may be exploited in the screening of new choline kinase inhibitors to evaluate their antimalarial activity.
Asunto(s)
Colina Quinasa/química , Plasmodium falciparum/enzimología , Adenosina Trifosfato/química , Secuencia de Aminoácidos , Animales , Caenorhabditis elegans , Eritrocitos/metabolismo , Humanos , Cinética , Modelos Moleculares , Datos de Secuencia Molecular , Fosforilcolina/química , Conformación Proteica , Homología de Secuencia de AminoácidoRESUMEN
[reaction: see text] A mild, efficient, one-pot protocol for the cyclization of nitro-aryl substrates using SnCl(2) has been described. The mechanistic course of the reaction suggests the involvement of a hydroxylamine intermediate leading to an intramolecular cyclization via N-N bond formation. The versatility of the methodology has been demonstrated by using two nitro-aryl substrates derived from dihydroisoquinolines and dihydro-beta-carbolines. The intramolecular cyclization led to the formation of indazoles in high yields and purities.
RESUMEN
The needles of Taxus wallichiana gave a taxoid 1-hydroxy- 2-deacetoxy-5-decinnamoyl-taxinine j, whose structure has been established by spectroscopic data and confirmed by X-ray crystallography. The taxoid possesses significant cytotoxic and immunomodulatory activity.
Asunto(s)
Antineoplásicos/farmacología , Factores Inmunológicos/farmacología , Taxoides/farmacología , Taxus/química , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Concanavalina A/farmacología , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Factores Inmunológicos/química , Factores Inmunológicos/aislamiento & purificación , Linfocitos/efectos de los fármacos , Modelos Moleculares , Conformación Molecular , Taxoides/química , Taxoides/aislamiento & purificación , Vinblastina/farmacología , Vincristina/farmacologíaRESUMEN
Comparative X-ray diffraction analysis of 5,6,7,9-tetra-O-acetyl-4,8-anhydro-1,3-dideoxy-D-glycero-L-gluco-nonulose (1) and a structurally related analog, 1,2,3,4,6-penta-O-acetyl-beta-D-galactopyranose (2), are reported. Both crystals have one molecule in the unit cell and the pyranose rings in both exist in the 4C1 conformation.
Asunto(s)
Galactósidos/química , Monosacáridos/química , Cristalización , Cristalografía por Rayos X/métodos , CalorRESUMEN
Various 6-aryl-3-cyano/methoxycarbonyl-4-methylsulfanyl-2H-pyran-2-ones have been synthesized as a potential substitute of 2,4-thiazolidinedione head group to express potent PPAR-gamma transactivation response. Some of the screened compounds have shown promising PPAR-gamma agonistic activity.
Asunto(s)
Nitrilos/farmacología , PPAR gamma/efectos de los fármacos , Piranos/farmacología , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Ligandos , Modelos Moleculares , Estructura Molecular , Nitrilos/síntesis química , Nitrilos/química , PPAR gamma/agonistas , Piranos/síntesis química , Piranos/química , Relación Estructura-ActividadRESUMEN
The mechanism of antimalarial activity of clotrimazole was studied placing emphasis on its role in inhibiting hemoperoxidase for inducing oxidative stress in Plasmodium falciparum. Clotrimazole, in the presence of H2O2, causes irreversible inactivation of the enzyme, and the inactivation follows pseudo-first order kinetics, consistent with a mechanism-based (suicide) mode. The pseudo-first order kinetic constants are ki = 2.85 microM, k(inact) = 0.9 min(-1), and t(1/2) = 0.77 min. The one-electron oxidation product of clotrimazole has been identified by EPR spectroscopy as the 5,5'-dimethyl-1-pyrroline N-oxide (DMPO) adduct of the nitrogen-centered radical (aN = 15 G), and as DMPO protects against inactivation, this radical is involved in the inactivation process. Binding studies indicate that the clotrimazole oxidation product interacts at the heme moiety, and the heme-clotrimazole adduct has been dissociated from the inactivated enzyme and identified (m/z 1363) by mass analysis. We found that the inhibition of hemoperoxidase increases the accumulation of H2O2 in P. falciparum and causes oxidative stress. Furthermore, the inhibition of hemoperoxidase correlates well with the inhibition of parasite growth. The results described herein indicate that the antimalarial activity of clotrimazole might be due to the inhibition of hemoperoxidase and subsequent development of oxidative stress in P. falciparum.